Sarah Berga - From adolescence through menopause

In my training I am really a neuroscientist, in my practice every day I see patients who nobody else wants to take care of anymore. I am asked to solve all sorts of unusual endocrine problems. We make a lot of diagnoses and a lot of referrals to standard endocrinologists because we find a lot of endocrine disease in our infertility and endocrine populations. Really the inspiration for today’s talk is to teach everyone a little endocrinology who wants to lean it. I never try to force anyone into this but it is important to understand that not all hormones are the same and how to use them wisely.

As you know there are lots of recommendations out there and if you just actually collate the entire universe of recommendations you will be incredibly confused. Part of actually being able to sift and sort through the recommendations is understanding some of the biology. I am actually going to focus a little bit on physiology as it relates to stage of life because I think that is part of the problem as well. Each stage of our reproductive life actually has different hormonal patterns. When you are in the adolescent and reproductive years, as we have just heard from Enda, you are really interested in fertility sparing and enhancing surgeries. You have to grapple with the issue of whether or not to do oocyte preservation. You have to think about hormonal suppressive techniques that you might want to employ and whether or not they actually work for pain relief if that is one of the issues.

When it comes to the perimenopause and menopause it is even more confusing. There is very little guidance out there. I think what people do not recognize is the hormonal swing to the perimenopause may in fact exacerbate some of the underlying problems that one has, whatever those are. And in the case of endometriosis it can exacerbate the presentation and complicate the treatment.

One of the issues is that when we give hormones to people who are a little bit older they actually do not have the same side effect profile as they did when they were younger. Age changes everything. Just think about an aging cell, the telomeres are different, the growth factors that play upon that cell are different and cells do not respond to hormones in exactly the same way because in fact they are not the same. Their DNA is changed with time and there is really an ontogeny that exists inside the nucleus that says how old that cell is. We know this for eggs but it is actually true for other cells as well.

One of the most pressing issues I think is whether or not the hormones we give will reactivate dormant lesions if there are some and whether or not we have to worry about the risk of malignant transformation. This is a big one. Everybody is really nervous about what to do after you are in the perimenopause or are menopausal and whether or not you can use hormones. As if the topic were not already controversial enough now you have got the additional wrinkle of thinking about it in the context of a woman with endometriosis.

These are the kind of the standard ways of thinking about reproductive stage. We tend to track it by menstrual cycle length but there is a lot of complexity that lies beneath the surface on this. The standard menstrual cycle, the one that is in everyone’s head, is shown here. It starts in the brain. I taught sex-ed to fourth graders and we pasted in the reproductive body parts including the hypothalamus. I got back letters, thank you notes, from the fourth graders with the word hypothalamus correctly spelt and I raised the bar for the medical students ever after. If fourth graders can master this concept everybody else can too. They were very – I said the best time to teach reproductive biology is before you really need to learn it. Fourth graders are the best audience I ever had.

When we have a reproductive system that is working in the classic manner you obviously can see what is happening to the endometrium and all of you I think know most of this.

But what happens next is a little bit more of a mystery for most people. The perimenopause is this ill-defined stage of life that begins at the end of reproductive life but before menopause. Menopause is easy to define and reproductive life is somewhat easy to define and perimenopause defies easy description because it is all about change. When you are thinking about the perimenopause you have to remember that the ovary is aging, the hypothalamus is aging and the body in between is aging. The timing and the tempo of menopause and perimenopause are going to be determined by oocyte quantity and quality but for this to really work right the brain has to be in the theme as well.

Gershon Weiss years ago showed in JAMA that in fact the hypothalamic feedback loop alters with time. The amount of estradiol that it takes to suppress GnRH and FSH is different at different stages of life. In fact it is the release from that inhibition that allows for puberty. It should not surprise us that in fact the feedback loop sensitivity changes with time. As we get older the FSH does not have the same effect on the oocytes as well. Both things are changing in both directions. You have altered feedback and you have ultra-responsivity at the level of the ovaries.

There are two little phrases that I have introduced to help people understand this and you see these all the time but you may not recognize them. One is called a loop cycle and this came out of the UK prospective longitudinal trials or studies on perimenopausal transition. So what is a loop cycle? It is a luteal out-of-phase follicular event. And what that means is before one cycle ends another can begin. So what you think of is the cycle comes to the end and there is a menstruation and another follicle starts to develop and that is not what is happening in the perimenopause. One is coming along, another is coming along and if you do IVF for a living this should not shock you because you can start a cycle any time you want with a little bump in FSH. There is no reason to think you cannot get a follicle that gets a little bump of FSH in the luteal phase. I know that people were taught that progesterone will inhibit follicle development. All progesterone normally does is inhibit FSH. But as you get older FSH rises so you can bump off a waiting follicle and you can have a two for one but not synchronized cycle just like we sometimes see when we give FSH to stimulate.

The other is lag cycle. This is my favorite because people will have a month or two where things are quasi-menopausal in terms of symptomatology and then they will be fine for a while. Then they will have another spell. I had a waiting list of a pretty long time and people will say, “When I made this appointment I felt terrible and now I feel okay. When is the next time I will feel terrible again?” Well that I do not really know but I can explain to you why you were feeling terrible, I just do not know when the next time is going to be.

The most clinically evident sign of perimenopause is the change in menstrual cycle interval and that is easy for us to track and that is what we do in these longitudinal studies. But what is happening before the menstrual cycle interval changes is really interesting as well.

I was the reviewer for this paper many years ago and this is Nanette Santoro’s beautiful trial or study. These are women who are about 15 years apart by age and they are still reporting regular menstrual cycles. If you look at LH it is actually standardized to the LH surge. And you can see FSH in the urine is much higher in the open circles and those are the older women. If you look at the estrone that is the surrogate or the metabolite for estradiol in the urine and you can see in the older women it is higher. If you look at progesterone in the older women it is lower even though their cycles are roughly the same length. If you look at the follicular phase look at LH and look at FSH, it is shorter. What do you think that would do to endometrial tissue? It would probably send a grow signal, right? It will send a grow signal to the endometrium and women present with heavy menses that they cannot predict and some of the time that progesterone little bump there is missing altogether. So those cycles do not actually have very good flow characteristics.

Then comes the lag cycles. I love this one. I love this one because it was published in 1976 – how many of you were alive in 1976? Oh, that is good that makes me feel a little better. I graduated from college in 1976 and it was our bi-centennial. If you look, I actually doctored this slide a little bit. If you look at the FSH you will see it is all over the map. What is the probability that you are going to know what stage of reproductive life a woman is in if you draw a random FSH? She is 46 and those little hatches at the bottom are her menstrual periods that year. And how many of those cycles are ovulatory? The bottom panel is progesterone. Uno – one. Okay, so one ovulatory cycle out of four in a year. How high is the estradiol level in the ovulatory cycle compared to the anovulatory cycles? Lower. What is happening to the endometrium regardless of where it rests under that milieu? Grow, it is going to grow, right? Unless it is really aberrant it is going to grow. It has gotten a nice big estradiol signal for a year. So women in their 40s are hyper estrogenic and they have less progesterone with each menstrual cycle they may have no progesterone. It should not surprise us that they have aberrant menstrual flow and have menorrhagic cycles. I think what is surprising to people is that the progesterone is low and the estrogen is higher than ten years before. That can cause problems with all sorts of tissues that are hormone responsive.

A big debate in the field is what happens to androgens at the time of perimenopause and Henry Burger is really the guru of this topic. He wrote a nice review article a couple of years ago and published it in Human Reproduction Update and I really recommend it to all the students, anybody who wants to actually have a quick read about what happens with physiology at the time of perimenopause.

The testosterone levels, how would you describe those? Across the menstrual – so zero is the final menstrual period. That is the no change part of the universe. So the follicles are dying but the rest of the apparatus in the ovary is not. So the theca cells are not completely dead and they continue to make androgens pretty much indefinitely.

We are trying to figure out from AMH when follicles are coming to an end but the rest of the ovary is not coming to the end. That I think is an important point as a reproductive endocrinologist to appreciate that ovaries actually play an endocrine role maybe indefinitely.

I hope I have convinced you that you cannot get there really easily in terms of guessing the stage of life because each of those follicular events in that 46-year-old woman was independent of the other and she did not know and I did not know and you will not know what is coming around the corner until it is all over.

So what is the big picture? We do tend to recommend hormone therapy for women who have had premature menopause and there are exceptions whether it is due to surgery or they have actually just gone through premature menopause. Sometimes we induce medical menopause and we have to decide what we are going to do about add back. This is a really highly controversial topic and when we are thinking about endometriosis we have to make it more complicated because we know there can be such a thing as we call progestin resistance. Hormones may not actually activate the same set of nuclear pathways in endometriotic cells as they do in endometrium. We have not really woven that into our thinking. But that is what you have to do to think about whether or not you are going to reactivate dormant lesions and whether or not there is any risk of malignant transformation from the hormonal exposure. There may be some from just the actual presence of the cells themselves.

Our sources of evidence are many, weaving them together is hard. The armamentarium is large but poorly understood. My favorite line for all of this complexity is not all estrogens are the same and if you want to know of the detail come and do a three year fellowship with us. We would be happy to teach it to you. I say that because really it is a wealth of information out there about how estrogens differ as well as all the other hormonal like compounds that are available now. And then there are all these non-hormonal options. This actually is a career, this is not a talk. This is a career and you really have to know a lot to do it well. You can put it together in a lot of different ways and you have to be nimble and flexible in the office. It is not a good place for dogmatism. If you need to be dogmatic you need to do something else because you really have to adjust the therapy to the patient in front of you and listen to her responses to it.

There are a few other tissues I like to think about when I am seeing patients. I happen to have a preference for the brain and so I like to weave that into our thinking. But of course women do not want to be bleeding and we have to weave that into our thinking as well. Understanding how progestins actually impact the endometrium when they are progestin dominant is really I think the Achilles Heel of our approach in the office and understanding what breakthrough bleeding is, understanding how a Mirena might actually be better and I do not have time to really explain all that.

There is very little guidance as suggested for the perimenopausal and menopausal patient. This was actually the only real guidance that is out there and this is from EMAS. NAMS has some guidance about this but not so much. There are some meta-analyses that can guide you for add-back HRT for the treatment of endometriosis. When used in conjunction with an agonist and this one suggested that actually no harm and perhaps benefit from using GnRH agonist plus add-back. This was a systemic review of dienogest for endometriosis and really I think the bottom line of this study was that there were very few head to head comparisons of dienogest with anything else so it was hard to make a conclusion even though it looked like it was maybe working as compared to a GnRH agonist.

Studies on recurrence are the rarest. You put this is your typical pub-med and you do not get very much. And some of it is actually hard to find. This is an older study from John Rock’s group when he was at Emory looking at women who had had a TAH BSO for endometriosis and I know that you have to weave in here the completeness of the surgery to really understand this better. But at least in women who seemed to be pain free at the time you could add hormones back in and not make them worse. But if they were already in pain then you had to be careful because then you had a relative risk of reoperation of 8.1. It is not a risk free strata to find yourself in.

This is another one, a cohort of 95 women and there was a low recurrence rate of 20 percent over ten years whether or not you initiated ERT immediately after surgery or waited for six weeks. Here is another one. And the risk of recurrence was increased if there were residual peritoneal implants greater than 3 cm, which I think of course makes sense.

Studies on malignant transformation are listed here. They are the ones I could find and some of you probably know this literature better than I do. It is low but not zero. I think we do not understand what would make an endometriotic lesion at risk for malignant transformation and whether or not progestin use would actually reduce that risk. So if you are going to give HRT after menopause should you give progestins because of this rare risk? When we understand that progestins actually have other risks including the risk of breast cancer and mood, sort of mood compromise in some then you have to really balance the pros and cons. I think a lot of people suggest the following: first of all there are lots of information gaps and it is good to be honest about that with patients because I think they appreciate it even though they might feel a little frustrated or left out it is better to say we do not know everything we need to know to do this well. I hold out hope for the molecular approach. I am really worried about progestin resistance and so that actually dampens my enthusiasm for using it because I do not know that I am going to get what I want anyway.

The art of HRT is to weave the patient’s circumstance into a good understanding of what hormones do and do not do and understand what the patient’s goals are in the context of the disease in front of you including endometriosis. Remember they may have other autoimmune like conditions and other symptomatologies that you have to weave in. But the one that worries me the most is that progestins tend to be mood suppressing. I do not know what the long term natural history is of progestin over-exposure after menopause, I bet you it is not good. Some of that is based on work we do on monkeys and I do not have time to review right now but if you can be in an estrogen only paradigm going forward in a low dose manner I think that is good.

What I recommend for most patients who are menopausal and beyond is a low dose of transdermal estradiol. I do not have time to really review why that is the better, the safer recommendation but I wanted to just kind of do a whirlwind tour of some of the high level concepts that you should be thinking about. When you see the patient who is post-reproductive who has got endometriosis because although her reproductive questions may have come to an end the rest of her has not and there are just as many questions that await the next stage of her life as did the previous stage of life.

Thank you so much for inviting me here it has been a great conference. Thanks Lone for organizing this. Thanks Tamer for all your hospitality, for bringing us all together. I have learned a lot. It has really been an honor and a privilege to participate, thanks again to everybody.

I can see only the halo over your head but I think it is Enda.

Enda McVeigh, MD: It is not a halo, I do not have a halo. Thank you. I thought – are you going to be redundant …the future? If we look at Jonathan Tilly’s work where he had the precursor cells, the cortex, and then…signs which is now a Nasdaq company that is equitized up to $400 million, I believe, and they have done no therapeutic work. Are we going to remove the menopause by reintroducing these precursor cells back into, what you I think very rightly described as a functioning organ in the menopause which we think a lot of people forget about and remove the ovaries too quickly in the menopause. Might that occur, to finish with.

Sarah Berga, MD: Yes, I do not know. Do we want to do that? We have a guy working on that in our shop too and I am his advisor. I have not asked him if we want to do this because he wants to do that. Yes, fertility forever or estrogen forever? You know there are a lot of very good pharmaceutical preparations that can get you mostly what you want for very little effort. I think creating an artificial ovary would be slick. But I do not know how utilitarian it would be in the long run. I think oocyte vitrification is a far slicker thing to do for now. I mean we recommend that to patients who are in certain predilections, right? I think that has been really nice to have because having to make embryos and freeze embryos when someone is not quite sure what they are doing – have the ongoing fertility side of this is really important. I still do that kind of stuff. I have an 18 year old tomorrow that I am going to have to egg retrieval on for vitrification and I am glad we have this to offer to her. But an artificial ovary? That sounds hard. Thank you.

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